Abstract ? Project Summary Cognition Therapeutics Inc. (CogRx) has discovered CT1812, a novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in?class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer?s disease. CT1812 is an orally administered lipophilic isoindoline formulated as a fumarate salt that is rapidly absorbed and highly brain penetrant. It displaces receptor-bound Abeta oligomers by allosterically antagonizing the sigma-2/PGRMC1 receptor (Izzo et al., 2014a, b). CT1812 thus represents the first disease-modifying therapeutic that will test the oligomer hypothesis of Alzheimer?s disease. Such a drug candidate would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. This application proposes to assess the safety and pharmacokinetics of oral doses of CT1812 in a Phase Ib clinical trial in early Alzheimer?s patients. Successful completion of this Phase Ib safety trial will lay the groundwork for future studies of CT1812?s therapeutic effectiveness in larger Phase 2 trials in Alzheimer?s patients.